U.S. patent number 4,667,668 [Application Number 06/726,064] was granted by the patent office on 1987-05-26 for dosage inhalator.
This patent grant is currently assigned to Aktiebolaget Draco. Invention is credited to Kjell I. L. Wetterlin.
United States Patent |
4,667,668 |
Wetterlin |
May 26, 1987 |
Dosage inhalator
Abstract
A dosage inhalator for the inhalation of a pharmacologically
active compound in solution form is disclosed. The inhalator
comprises a propellant container, a propellant dispensing unit, and
a dosing unit for dosing the pharmacologically active compound. The
dosing unit comprises a storage chamber for the active compound, a
dose loading unit directly connected thereto, and a nozzle. The
does loading unit comprises a movable perforated membrane, and a
holder for the perforated membrane. The membrane is displaceable
between a first position where a solution of active compound is
introduced into the perforations of the membrane, and second
position where the perforations of the membrane are inserted into a
propellant passage. While the membrane is in the second position,
the propellant dispensing unit may be operated, allowing propellant
originally stored in the propellant container to remove the
solution of the active compound from the perforations inserted into
the propellant passage and carry said solution out the nozzle.
Inventors: |
Wetterlin; Kjell I. L. (S
Sandby, SE) |
Assignee: |
Aktiebolaget Draco
(SE)
|
Family
ID: |
20344221 |
Appl.
No.: |
06/726,064 |
Filed: |
April 23, 1985 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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393720 |
Jun 30, 1982 |
4534345 |
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Foreign Application Priority Data
Current U.S.
Class: |
128/203.15;
128/203.23; 222/636 |
Current CPC
Class: |
A61M
15/0065 (20130101); A61M 2205/8225 (20130101); A61M
11/02 (20130101); A61M 2202/064 (20130101) |
Current International
Class: |
A61M
15/00 (20060101); A61M 015/00 () |
Field of
Search: |
;128/203.23,203.15
;604/57,58 ;222/345,347,636 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Coven; Edward M.
Attorney, Agent or Firm: Brumbaugh, Graves, Donohue &
Raymond
Parent Case Text
This aplication is a division of application Ser. No. 393,720 filed
on June 30, 1982, now U.S. Pat. No. 4,534,345.
Claims
What we claim is:
1. An inhaler for administering a solution of a phramacologically
active compound to a patient as droplets suspended in a propellant
comprising:
a gas conduit through which a dose of said solution suspended in
said propellant is supplied to said patient, a storage chamber
means for storing said solution, a perforated membrane having a
plurality of preselected portions each adapted to hold and dispense
a reproducible unit dose 'less than 50 mg of said compound in
solution, and a propellant supply unit for supplying a
pharmacologically acceptable propellant to the inhaler,
said conduit, membrane and propellant supply unit being operably
connected to each other so that propellant released from the
propellant supply unit passes through one of said preselected
portions of said perforated membrane that is positioned across said
gas conduit, releases said solution carried thereby, and carries
said solution as suspended droplets through said gas conduit to the
patient,
wherein said perforated membrane is adapted to be displaceable
through a plurality of positions in each of which another
preselected portion thereof holding a reproducible dose of said
solution is moved into a dispensing postion relative to said gas
conduit and propellant supply unit, and another portion thereof is
moved into said storage chamber, and
whereby reproducible doses of the solution can be transferred from
said storage chamber means by said membrane, positioned across said
gas conduit by said membrane, and removed therefrom by propellant
discharged from said propellant supply unit.
2. An inhaler according to claim 1 wherein the perforated membrane
is displaceably arranged for rotation relative to the storage
chamber.
3. An inhaler according to claim 1 wherein said perforated membrane
is a rotatable drum.
4. An inhaler according to claim 1 including a dosing chamber,
first passage means connecting said propellant supply unit to said
dosing chamber for passage of propellant therebetween, and second
passage means connecting said dosing chamber to said perforated
membrane for passage of propellant therebetween, first valve means
in said first passage for controlling the flow of propellant
therethrough, and second valve means in said second passage means
for controlling the passage of propellant therethrough,
said first and second valve being arranged so that only one valve
may be opened at any one time, said first valve when opened
allowing propellant stored in said propellant supply unit to flow
into said dosing chamber and when closed prohibiting said flow, and
said second valve when opened allowing propellant stored in said
dosing chamber to flow into said propellant passage and when closed
prohibiting said flow into said passage,
whereby the amount of propellant discharged for each dose is
controlled by the amount of propellant stored in said dosing
chamber.
5. An inhaler according to claim 4 including a tilting lever
adapted to interconnect said first valve and said second valve such
that only one of said valves may be opened at any one time.
6. An inhaler according to claim 5 wherein each of said valves
includes a spring biasing the valve to its normally closed
position.
7. An inhaler according to claim 1 wherein each preselected portion
has a plurality of perforations of substantially the same size,
each such perforation being adapted to hold and dispense a share of
the dose dispensed by said preselected portion.
8. A dosing unit adapted for use in an inhaler for administering to
a patient a unit dose of a solution of a pharmacologically active
compound suspended in the form of droplets in a propellant through
a gas conduit, said propellant being supplied from a propellant
supply unit to said gas conduit through propellant conduit means,
comprising:
a storage chamber means for storing
said solution;
a perforated membrane adapted to hold and dispense said solution in
a plurality of preselected portions adapted to hold a reproducible
volume of said solution, including at least a first and second
portion;
holding means for holding said first portion of said membrane in a
loading position in said storage chamber means and adapted to hold
said second portion of said membrane in a dispensing position
between said gas conduit and said propellant conduit means; and
means for displacing said membrane on said holding means so that
said first portion of said membrane can be moved into said
dispensing position as said second portion can be moved into said
loading position,
whereby a controlled amount of the solution can be loaded from said
storage chamber means into one of said preselected portions and
transported by said displacing means to a position from where it is
adapted to be removed by propellant flowing through said propellant
conduit means and said gas conduit passage thereby to the
patient.
9. A dosing unit according to claim 8 wherein the perforated
membrane is displaceably arranged for rotation relative to the
storage chamber.
10. A dosing unit according to claim 8 wherein said perforated
membrane is a rotatable drum.
Description
FIELD OF THE INVENTION
The present invention relates to a new dosage inhalator intended to
be used at inhalation of pharmacologically active compounds. The
invention also relates to a new dosage unit for measuring dosages
of the active compound in solid, micronized form or in
solution.
BACKGROUND OF THE INVENTION
Special requirements are made with regard to dosage inhalators
intended for local administration of drugs to the respiratory tract
and to the lungs. Since mostly very potent drugs are to be
administered, the dose accuracy must be great. The dosage of active
compound that is to be administered may be as small as 0.1 mg. It
is also necessary that the particles that leave the dosage
inhalator have a suitable size distribution, since too big
particles tend to be deposited in the mouth.
Several systems are available for local administration of drugs to
the respiratory tract and to the lungs. Among these systems may be
mentioned nebulizing devices, powder inhalators which are activated
by the air flow generated at inhalation, pressurized aerosols and
pump inhalators.
The available systems work but are not without disadvantages.
The nebulizing devices, which are driven by a compressor, by
compressed gases or by ultrasound, are relatively big and bulky and
are mainly intended for stationary use. They are complicated to
use. The drug administration must continue during a fairly long
period of time, 5 to 10 minutes.
The use of powder inhalators has been increasing during the last
few years. They are activated by the air flow generated at
inhalation. When the patient inhales through the inhalator the
active compound in solid, micronized form, usually kept in a
capsule, is mixed with the inhaled air and administered to the
respiratory tract and to the lungs of the patient. These inhalators
require, of technical reasons connected with the dispensing of the
active compound, a fairly great amount of active compound, 20 mg or
more, in order to give an acceptable dosage accuracy. They are,
therefore, only useful for low-active compounds, or for high-active
compounds in combination with diluting agents, usually lactose.
They are cumbersome to load and to clean, and as a rule several
inhalations are necessary in order to empty a capsule. Furthermore,
they are difficult to handle for certain categories of patients,
and the diluting agent, lactose, is irritating at inhalation and
may cause increased frequence of caries.
The pressurized aerosols are today most widely used at ambulatory
treatment. Normally, they comprise a pressure unit that contains
the propellant, most often different types of halogenated
hydrocarbons, e.g. Freon.RTM., together with the active compound
which either is dissolved in the propellant or suspended in the
propellant in solid, micronized form. Dosage aerosols where a unit
dosage of the active compound is kept separated from the propellant
have also been described. Usually surface active compounds and
lubricating agents are added in order to obtain a suspension which
can be stored and in order to make the dosage mechanism work. The
propellants, most widely used, may, furthermore, have undesirable
toxicological and environmental effects.
The so called pump inhalators, finally, make use of compressed air
as propellant. The active compound is normally in the form of a
solution. The compression of the air is obtained by a piston
system, but it is difficult in a simple manner to generate a
pressure which is sufficiently high to permit an adequate particle
size distribution. Furthermore, it is difficult to obtain an exact
measuring of dosages of the active compound.
DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides a new dosage
inhalator intended for inhalation of pharmacologically active
compound in solid, micronized form or in solution, said dosage
inhalator comprising
(a) a propellant container and a propellant dispensing unit;
and
(b) a dosing unit for dosing the pharmacologically active
compound,
characterized in that the dosing unit for dosing the
pharmacologically active compound comprises a storage chamber for
the active compound directly connected to a dosing unit, said
dosing unit comprising a perforated membrane, a holder for the said
perforated membrane, and means for displacing the membrane, whereby
the membrane is displaceably arranged between a first position
where active compound is introduced into the perforations in part
of the area of the membrane and a second position where the said
part of membrane is inserted in the propellant passage.
This dosage inhalator has the following advantages;
1. No lubricating agents need to be used.
2. Active compound in an amount from 0.1 mg, in solid micronized
form or in solution, can be dispensed with sufficient accuracy and
without need for use of diluting agents for active compound in
solid micronized form.
3. The quality of the generated aerosol is independent of the
breathing capacity of the patient.
4. Propellants under high pressure, for example liquid carbon
dioxide, can be used. Thereby a particle size distribution at
administration of active compound in solution can be obtained which
is better than the particle size distribution which is obtained
with a pump inhalator.
5. An atoxic propellant can be used, for example carbon dioxide in
liquid form or in solution.
In a further aspect, the invention relates to a new dosing unit for
dosing in a dosage inhalator of pharmacologically active compound
in solid micronized form or in solution. The said dosing unit is
characterized in that it comprises a storage chamber for the active
compound in connection with a dosing unit which comprises a
perforated membrane, a holder for said perforated membrane, and
means for displacing the said membrane, whereby the dosing unit and
the perforated membrane are displaceably arranged in relation to
each other between a first position where active compound is
introduced into the perforations in part of the area of the
membrane and a second position where the said part area of membrane
is introduced in the propellant passage of the dosage
inhalator.
The dosing unit will admit dispensing active compound in solid,
micronized form or in solution with sufficient dosage accuracy in
an amount of from 0.1 to 5 mg. Also dosages in an amount of from 5
to 50 mg can be dispensed, especially when the active compound is
in solid micronized form. The dosing unit according to the
invention can be used in dosage aerosols which are activated with
propellant under pressure, as well as in inhalators intended to be
activated by the air flow generated at inhalation.
In a further aspect, the invention relates to the use of a
perforated membrane as dosing unit for active compound in solid,
micronized form in dosage aerosols.
In the preferred embodiment of the dosage inhalator and the dosing
unit of the invention, the active compound is used in solid,
micronized form.
Specific embodiments of the invention will now be described in
detail with reference to FIGS. 1, 2, 3, 4, 5, 6, 7 and 8.
FIG. 1 is a section through a dosage inhalator for solid,
micronized active compound, activated with propellant under
pressure.
FIG. 2 is a section through a variant of the dosage inhalator of
FIG. 1 for administering the active compound in solid, micronized
form.
FIG. 3 is a section through a dosage inhalator for administration
of active compound in solution, activated with propellant under
pressure.
FIG. 4 is a section through a variant of the dosage unit intended
for dosing active compound in solution.
FIG. 5 and FIG. 6 illustrate embodiments of the valve in the dosing
unit for propellants which is part of the dosage inhalators
according to FIG. 1, FIG. 2 and FIG. 3.
FIG. 7 shows scrapers in the storage chamber, which scrapers are
used to introduce solid, micronized active compound into the
perforations in a horizontal perforated membrane.
FIG. 8 shows how solid, micronized active compound is fed from the
storage unit into the perforations in the perforated membrane using
the said scrapers.
A. Dosage Inhalator for Solid, Micronized Active Compound (FIG. 1
and FIG. 2)
The dosage inhalator comprises three main components:
(a) a dosing unit 23 for dosing the pharmacologically active
compound.
(b) a propellant container 1 intended for liquid and gaseous
propellant.
(c) a propellant dispensing unit 2 intended for dispensing the
propellant.
The propellant container 1 is manufactured in a material, for
example steel, which makes it possible to use the propellant
container for liquid propellants, for example halogenated
hydrocarbons, and liquid carbon diozide, and for gaseous
propellants. Its construction will admit use of carbon dioxide as
propellant, in liquid form and in gaseous form, in spite of the
high pressure, 49.5 bar at 15.degree. C., which is required to keep
carbon dioxide in liquid form. The propellant container 1 is
arranged to be connected to the propellant dispensing unit 2, by a
threading.
The propellant container unit comprises a first valve 3 which is
arranged in the discharge passage from the propellant container 1.
The valve 3 is so arranged that it automatically closes the
discharge passage from the propellant container 1 when the said
container is removed from the propellant dispensing unit 2. The
valve 3 which is loaded with a spring 4, comprises a displaceable
connecting arm 5 which co-operates with a tilting lever 6. The said
tilting lever is movable around an axis 7. The valve part of the
connecting arm 5 is provided with a protrusion 8 which co-operates
with a depression 9 in the propellant unit 1. In the depression 9 a
sealing ring 10 with rectangular section is arranged, see FIG. 5. A
connecting passage 14 for propellant is arranged from the passage
in which the connecting arm 5 is arranged to the dosing chamber 15
in the dosing unit 2. O-rings 16, 17, 18 and 19 seal where the
connecting arm 5 attaches to the tilting lever 6 and where the
connecting passage 14 reaches the propellant dispensing unit.
The passage 14 leads to a dosing chamber 15. The dosing chamber 15
comprises a spring loaded valve 20, constructed in the same manner
as the valve 3 in the propellant container 1. The valve 20
comprises a movable connecting arm 21 which co-operates with the
tilting lever 6.
From the dosing chamber 15 a passage 22 leads to the dosing unit
23. The dosing unit 23, which in FIG. 1 is illustrated for
dispensation of solid, micronized compound, comprises a storage
chamber 24 for the active compound directly connected with a dosing
unit comprising a perforated membrane 25 in the form of a drum, a
holder 26 for the membrane, and means for displacing the membrane,
whereby the membrane is displaceably arranged between a first
position where active compound in solid, micronized form is
introduced into the perforations in part of the area of the
membrane, and a second position where the said part of the membrane
area containing a defined amount of active compound is introduced
in the propellant passage 22. Active compound is brought from the
storage chamber 24 into the perforations in the membrane using
elastic spring-loaded scrapers 27.
In one preferred embodiment, the perforated membrane in the dosing
unit 23 can be designed, as in FIG. 1, as a drum-formed rotating
membrane, where the active compound is pressed into the
preforations using spring-loaded scrapers 27 when the drum is
brought to rotate. In another preferred embodiment, the membrane
25, see FIG. 2, is designed as a rotating disc connected to the
storage chamber 24. The active compound is in this embodiment
pressed into the perforations in the membrane using a spring-loaded
plate 29. The perforated membrane 25 is rotated using turning means
30 so that part of the membrane area with its perforations loaded
with active compound is introduced into the propellant passage 22.
The turning means 30 in FIG. 2 comprise spring-loaded pins 40 which
engage in dents in the perforated membrane 25 as is shown in FIG.
7.
In use the dosage inhalator according to FIG. 1 and FIG. 2 will
operate as follows. The valve 3 in the propellant container 1 is
opened by depressing the portion of the tilting lever 6 which is
situated in connection with the valve 3, using a trigger 31. When
the valve 3 is open the propellant, which can be in liquid or
gaseous form, passes from the propellant unit 1 along the sides of
the connecting arm 5 and via the passage 14 to the dosing chamber
15. The dosing chamber 15 is filled with propellant. When the
pressure on the tilting lever above the valve 3 ceases, the valve 3
is closed by action of the combined pressure from the propellant in
the propellant container 1 and the spring 4 in the valve 3. Now the
valve 20 is opened by depressing, using the trigger 32, that part
of the tilting lever 6 which is situated in connection with the
valve 20, whereupon the propellant in the dosing chamber 15 and the
propellant in the passage 14 passes along the sides of the
connecting arm to the valve 20 and via the passage 22 to the dosing
unit 23. The propellant will here pass that part area of the
perforated membrane 25 in FIG. 1 respectively FIG. 2 which has been
introduced into the propellant passage and will remove the active
compound which had been loaded into the perforations in the
membrane. The active compound will be driven out through the nozzle
28.
By the co-operation between the tilting lever 6 and the valves 3
and 20, the connection between the propellant container 1 and the
dosing chamber 15 will be broken before the valve 20 of the dosing
chamber 15 can be acted upon and the metered amount of propellant
discharged. Thus, the construction of the tilting lever will admit
only one of the valves 3 and 20 in the propellant container and in
the dosing chamber, respectively, to be open at a given time. Both
valves cannot be open simultaneously. The construction of the valve
3 in the propellant container is such that it will always be closed
when the propellant container is released from the propellant
dispensing unit.
In an alternative embodiment of the valves 3 and 20, see FIG. 6,
the propellant unit can be provided with a protrusion 11 which
co-operates with an opposite depression 12 in the valve part of the
connecting arm 5. In the depression 12 a sealing ring 13 with
rectangular section is arranged.
The valve construction utilized in the valves 3 and 20, see FIGS. 5
and 6, is an important part of the dosage inhalator, because this
valve construction makes it possible to use propellant under high
pressure, for example liquid carbon dioxide, without risk for
leaking.
B. Dosage Inhalator for Active Substance in Solution (FIG. 3 and
FIG. 4)
The dosage inhalator according to FIG. 3 differs from the dosage
inhalator according to FIG. 1 only with respect to the dosing unit
for the active compound, which in FIG. 3 is designed for dispensing
active compound in solution. The dosing unit is arranged with a
perforated membrane 33 which is arranged to be able to be displaced
from a first position, where the membrane is immersed in the
storage chamber 34 for active compound in solution, to a second
position where the membrane is placed in the propellant passage 22.
The membrane is operated with a spring-loaded trigger 35. O-rings
36 and 37 seal the connections between the membrane 33 and the
propellant passage 22.
FIG. 4 illustrates an alternative embodiment of the dosing unit for
active compound in solution. The storage chamber 34 for active
compound in solution is here connected with a second storage
chamber 38 where a greater volume of the solution of the active
compound can be kept. The membrane 33 can in the same way as in
FIG. 3 using the trigger 35 be brought into the storage chamber 34
and then be brought into the propellant passage 22.
The size of the dosing chamber 15 may vary. Its size will depend
upon whether liquid or gaseous propellant is to be dispensed. A
suitable size for liquid propellant, for example liquid carbon
dioxide, may be 25-300 .mu.l. For gaseous propellants, for example
gaseous carbon dioxide, a suitable size may be 50-1000 .mu.l.
The perforated membrane can be manufactured in any suitable
material, for example metal or plastic. The size of the dosage of
active compound which is to be administered is determined by the
size of the perforations in the membrane, the thickness of the
membrane, and the number of perforations that is brought into the
propellant passage, and by the area of the propellant passage. The
accuracy of the dosage will mainly depend on the accuracy in the
manufacturing of the membrane. Examples of perforated membranes
that can be used are the metal nets which are manufactured by Veco
Beheer B. V., Eerbeek, The Netherlands. These nets can be obtained
with various sizes of the perforations. They can be formed in
desired manner, for example in drum form or they can be used in the
form of horizontal, plane membranes. Also woven nets of metal,
fiber or of other materials can be used, especially at
administration of active compound in solution. The important factor
is the dosage accuracy that can be obtained.
At dispensing of active compound in solid, micronized form, it is
preferred that the perforations in the perforated membrane are in
the form of truncated cones with their larger area directed towards
the nozzle. Such a construction will partly facilitate the loading
of the membrane with active compound, partly facilitate the
emptying of the perforations when the active compound is
administered. See FIG. 8.
The perforated membrane, when it is in the form of a drum, can be
arranged for loading from the outside as well as from the inside of
the drum.
The perforations in the perforated membranes can be of arbitrary
design. They can be circular, square, elliptic, rectangular or have
other geometrical form. The area of the perforations in the
membrane can be a large or a small part of the membrane area, for
example from 1 to 95%, whereby the term "membrane area" refers to
that area of the membrane which is inserted into the propellant
passage. The number of perforations in the membrane area can vary
depending on factors such as the amount of active compound that is
to be administered per dosage, the physical properties of the
active compound, etc. In a preferred embodiment, the perforations
have conical shape, as said above, at dosing of solid, micronized
compound.
At administration of active compound in solution the construction
of the perforated membrane including the form of the perforations
is less critical. Also membranes in the form of nets, for example
woven nets in metal or in fiber can be used, as mentioned
above.
The size of the dosages of bronchospasmolytically active compounds,
or steroids for inhalation, that normally are administered at each
administration is as follows.
Terbutaline: standard dosage 0.5 mg
Salbutamol: standard dosage 0.2 mg
Budesonide: standard dosage 0.1 mg
The active compound can be administered in micronized form without
additional ingredients or in pharmaceutically modified micronized
form in order to obtain improved flow properties. The micronized
particles may be covered with a film functioning for example by
masking bitter taste of the active compound, or by providing slow
release of the active compound in the respiratory tract.
The dosing unit in the dosage inhalator according to the present
invention admits dispensing of an amount of active compound of
mainly from 0.1 to 1 mg, but also dosages from 1 to 5 mg and from 5
to 50 mg, especially when solid, micronized active compound is
used, can be dispensed by suitable design of perforations and size
of that part of the area of the perforated membrane which is
intended to be introduced into the propellant passage.
The storage chamber 24 for active compound in solid, micronized
form, respectively the storage chamber 34 for active compound in
solution can be intended to contain active compound for about 100
to 200 dosages, which is sufficient for about a month's normal use
for local administration of active compound to the respiratory
tract.
The storage chamber 24 for solid, micronized compound can be placed
above as well as below the perforated membrane. In a preferred
embodiment the storage chamber is placed above the membrane. The
storage chamber 24 can be arranged to be refilled via a sealable
opening 39.
The storage chamber 34 for active compound in solution is in one
preferred embodiment connected with a larger sealable storage
chamber 38.
In a preferred embodiment of the dosage inhalator according to the
invention the perforated membrane 25 is displaceably arranged in
relation to the storage chamber 24.
* * * * *